Lowered levels of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) have been reported in postmortem brain tissue specimens from suicide victims. Lowered levels of cerebrospinal fluid 5-HIAA have been reported in both depressed and relatively non-depressed patients who have made suicide attempts. We have reported increased density of cortical postsynaptic serotonin-2 (S-2) receptors in suicide victims. Since in the same series of suicide victims presynaptic imipramine binding sites were decreased in the frontal cortex, we postulate that decreased presynaptic serotonergic activity has resulted in secondary compensatory supersensitivity of the postsynaptic S-2 serotonin receptor. Whether net serotonergic transmission is decreased is difficult to prove however, our hypothesis is that reduced presynaptic serotonergic function contributes to the underlying pathophysiology of human suicidal behavior. We plan to test this hypothesis by a series of studies in postmortem brain tissue from (a) suicide victims (b) depressed patients dying from nonneurological diseases and (c) appropriate controls. We hope to (1) verify our serotonin receptor findings in a new series of suicide victims; (2) extend our studies of the serotonergic system by examining a number of brain regions and peripheral tissues, and including in addition to receptor assays, measures of 5-HT, 5-HIAA, and tryptophan hydroxylase; (3) measure other neurotransmitters, their metabolites, related enzymes and receptors to define the neurochemical specificity of the changes associated with suicidal behavior and/or depression; (4) to extend our studies of the serotonin, adrenergic, dopaminergic and muscarinic receptors through the technique of quantitative autoradiography; (5) to initiate a pilot study investigating whether the neurochemical findings are specific for suicidal behavior rather than Major Depression. These studies should define in detail the extent and specificity of the serotonergic changes in suicidal behavior in terms of: brain region versus systemic effects detectable in peripheral tissues; and compared to other neurotransmitter systems. The possibility that a highly specific alteration of the serotonergic system may underly suicidal behavior, independent of the presence of a Major Depression, has profound consequences for conceptualizing the basis of human behavior as well as important implications for developing an effective specific pharmacotherapy of this maladaptive behavior.